Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.

了解血小板抑制剂的药效作用是开发更有效的抗血栓疗法的标准。一个例子是急性冠脉综合征（ACS）的抗血栓治疗，特别是 ST 段抬高型心肌梗死（STEMI）患者，尽管使用阿司匹林和口服 P2Y12 抑制剂，但仍需要快速起效的强效抗血栓治疗。在这项研究中，我们评估了两种正在临床开发中的可注射血小板抑制剂（P2Y12 拮抗剂塞拉格雷和 GPIIb-IIIa 拮抗剂扎伦非班），它们可能适合 STEMI 患者的院前治疗。在代表临床相关血小板抑制水平（IC20-50%、1/2Cmax 和 Cmax）的抑制剂浓度下评估血小板反应性。光透射聚集测量法（LTA）用于评估聚集的初始速率（初级斜率，PS）和最大聚集（MA）。使用二磷酸腺苷（ADP）和凝血酶受体激动剂肽（TRAP）作为激动剂。当在 PPACK 或 TSC 中采集血液时，扎伦非班表现出类似的血小板聚集抑制作用，而塞拉格雷在 PPACK 中表现出更大的抑制作用。在这项研究中，使用 PPACK 抗凝剂、塞拉格雷和扎伦非班在所有测试的药物浓度下对 ADP 反应的 PS 影响相同。相反，与使用 TRAP 作为激动剂的塞拉格雷相比，扎伦非班在其 Cmax 浓度下具有显着更高的效力。在评估较低剂量的 MA 反应时，塞拉格雷对 ADP 反应的 MA 抑制作用比扎伦非班更强；然而，在代表 Cmax 的浓度下，这些药物是等效的。Zalunfiban 在 Cmax 剂量下对 TRAP 的反应也具有更大的 MA 抑制作用。这些数据表明，扎伦非班在减少血栓形成方面可能比塞拉格雷提供更大的保护，特别是因为凝血酶是血栓事件病理生理学中的早期关键主要激动剂。